Damage from chronic inflammation in the setting of inflammatory bowel disease has been linked to increased rates of small and large bowel cancer. Colonic inflammation is often associated with hemorrhage resulting in release of heme from damaged erythrocytes. Heme oxygenase-1 (HO-1) protects against oxidative DNA damage from heme. We hypothesized that deletion of intestinal epithelial cell (IEC) HO-1 would increase colitis associated tumorigenesis. Inflammation associated hemorrhage correlated with mucosal Hmox1 expression in a murine model of colitis, but conditional deletion of IEC Hmox1 (Hmox1ΔIEC) did not influence inflammatory outcomes. However, in a colitis associated cancer model, we unexpectedly observed decreased number and size of colonic tumors in Hmox1ΔIEC mice compared to controls. Single cell RNA sequencing revealed a similar tumor leukocyte profile, but the tumor epithelial population displayed increased colonocyte differentiation in Hmox1ΔIEC mouse tumors relative to stem/secretory epithelial populations. Deficiency of HO-1 also lead to increased cell death and cell cycle arrest in murine colonoids and colon cancer cells, which was exacerbated by heme. Findings define a previously unreported role for epithelial HO-1 in supporting tumorigenesis in the colitic microenvironment. US Department of Veterans Affairs This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.